OPA1 and MICOS Regulate mitochondrial crista dynamics and formation

Abstract

Mitochondrial cristae are the main site for oxidative phosphorylation, which is critical for cellular energy production. Upon different physiological or pathological stresses, mitochondrial cristae undergo remodeling to reprogram mitochondrial function. However, how mitochondrial cristae are formed, maintained, and remolded is still largely unknown due to the technical challenges of tracking mitochondrial crista dynamics in living cells. Here, using live-cell Hessian structured illumination microscopy combined with transmission electron microscopy, focused ion beam/scanning electron microscopy, and three-dimensional tomographic reconstruction, we show, in living cells, that mitochondrial cristae are highly dynamic and undergo morphological changes, including elongation, shortening, fusion, division, and detachment from the mitochondrial inner boundary membrane (IBM). In addition, we find that OPA1, Yme1L, MICOS, and Sam50, along with the newly identified crista regulator ATAD3A, control mitochondrial crista dynamics. Furthermore, we discover two new types of mitochondrial crista in dysfunctional mitochondria, “cut-through crista” and “spherical crista”, which are formed due to incomplete mitochondrial fusion and dysfunction of the MICOS complex. Interestingly, cut-through crista can convert to “lamellar crista”. Overall, we provide a direct link between mitochondrial crista formation and mitochondrial crista dynamics.

Emerging Roles of the MICOS Complex in Cristae Dynamics and Biogenesis

“…Recent studies using SR techniques showed unexcepted dynamics of cristae [24,66,68,[73][74][75]. Both cristae and CJs constantly changed their position within mitochondria, confirming that they are highly dynamic within seconds [24].…”

“…In recent years, many technical advancements that include live-cell imaging using super-resolution (SR) nanoscopy, focused ion beam-scanning electron microscopy (FIB-SEM), electron tomography (ET), single-particle tracking (SPT) and fluorescence recovery after photobleaching (FRAP) have been used to address the fundamental questions about cristae biogenesis and dynamics [24,25,[66][67][68]. These techniques have allowed unexpected insights into the dynamic nature of cristae and have changed our view of cristae being static entities that only display different shapes under varying circumstances.…”

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

“…Recent crystallographic and cryo-EM analyses of OPA1’s yeast homolog Mgm1, provide new insights into how OPA1 remodels the inner membrane to mediate fusion ( Faelber et al, 2019 ; Yan et al, 2020 ). In addition to facilitating inner-membrane fusion, OPA1 promotes dimerization of ATP synthase ( Patten et al, 2014 ) and interacts with the multisubunit Mitochondrial contact site and Cristae Organizing System (MICOS) to help mediate cristae organization in addition to remodeling of the inner membrane ( Hu et al, 2020 ; Stephan et al, 2020 ). Western blot analysis shows five distinct protein isoforms of OPA1: two long (L-OPA1) isoforms that mediate inner-membrane fusion and three short (S-OPA1) fusion-inactive isoforms.…”

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

“…However, Opa1 knockout (ko) mouse fibroblasts have also been extremely helpful in understanding the DOA pathogenic mechanism given the clear-cut phenotype due to the complete lack of the protein. Indeed, Opa1 null cells have no fusion activity ( 9 , 46 , 52 , 53 ), decreased the number of mtDNA and nucleoids ( 9 , 53 , 54 ), and caused profound alterations of cristae structure integrity ( 9 , 53 , 55 ). Furthermore, Opa1 ablation and OPA1 overexpression in mouse fibroblasts clarified the interplay between cristae and OPA1 in respiratory chain supercomplexe (RCS) assembly ( 56 ) and identified the ATP synthase as the effector of the OPA1-mediated protection of mitochondrial functions ( 57 ).…”